Palladium-catalyzed intramolecular carboacetoxylation of 4-pentenyl-substituted malonate esters with iodobenzene diacetate

Article abstract of DOI:10.1002/asia.201000194

The motorcyclization diaries: Palladium-catalyzed intramolecular carboacetoxylation of 4-pentenyl-substituted malonates proceeds with the aid of titanium tetraisopropoxide and iodobenzene diacetate. The transformation represents the first Pd^II/

Full text of DOI:10.1002/asia.201000194

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DOI: 10.1002/asia.201000194
Palladium-Catalyzed Intramolecular Carboacetoxylation of 4-Pentenyl-
Substituted Malonate Esters with Iodobenzene Diacetate
Daishi Fujino, Hideki Yorimitsu,* and Koichiro Oshima*[a]
Palladium-catalyzed difuntionalization reactions of al-
kenes are rapidly emerging as useful tools for synthesizing a
diverse range of complex molecules from rather simple al-
kenes.[1] Among them, oxidative processes involving a PdII/
PdIV cycle have attracted increasing attention recently owing
to their high efficiency as well as their mechanistic interest
(Scheme 1). Reactions that oxidatively introduce two heter-
ditions and report herein a new versatile intramolecular car-
boacetoxylation reaction, which yields acetoxymethyl-substi-
tuted cyclopentane derivatives 2.
Treatment of malonate 1a with iodobenzene diacetate in
the presence of titanium tetraisopropoxide and a catalytic
amount of [PdCl2ACHTNUTRGNEUNG(MeCN)2] in 1,2-dichloroethane (DCE) at
508C for 20 hours afforded the expected carboacetoxylation
product 2a in 49% yield, along with bicyclic lactone 3a in
14% yield (Table 1, entry 1).
Table 1. Screening of palladium catalyst and solvent.
Scheme 1. Palladium-catalyzed oxidative difunctionalization involving a
PdII/PdIV cycle. Nu1 and Nu2 represent nucleophiles. The oxidant may
contain a nucleophile.
Entry
Pd complex
[PdCl2A(MeCN)2]
[PdCl2A(MeCN)2]
[PdCl2A(MeCN)2]
[PdCl2A(MeCN)2]
[PdCl2A(MeCN)2]
[PdCl2A(MeCN)2]
[PdCl2A(MeCN)2]
Pd(OAc)2
[Pd(O2CCF3)2]
PdCl2
[Pd2A(dba)3]
none
Solvent
2a [%]
3a [%]
1
2
3
4
5
6
7
8
G
G
DCE
toluene
THF
DMF
AcOH
49
32
42
20
22
50
57
31
31
23
29
0
14
12
15
35
34
7
11
8
8
oatoms into alkene under PdII/PdIV catalysis include diami-
nation (Nu1, Nu2 =N),[2] oxyamination (Nu1 =N, Nu2 =O),[3]
and dioxygenation (Nu1, Nu2 =O).[4] On the other hand,
PdII/PdIV-catalyzed difunctionalization reactions that form a
carbon–carbon bond (Nu1 or Nu2 =C) have received less at-
tention.[5–9]
We envisioned that 4-pentenyl-substituted malonate esters
1 would undergo palladium-catalyzed oxidative cycliza-
tion.[10] Therefore, we investigated a variety of reaction con-
R
E
N
G
G
Ac2O
A
DCE/Ac2O (1:1)
DCE/Ac2O (1:1)
DCE/Ac2O (1:1)
DCE/Ac2O (1:1)
DCE/Ac2O (1:1)
DCE/Ac2O (1:1)
ACHTUNGTRENNUNG
9
N
10
11
12
4
4
0
N
G
[a] D. Fujino, Prof. Dr. H. Yorimitsu,+ Prof. Dr. K. Oshima
Department of Material Chemistry, Graduate School of Engineering
Kyoto University, Kyoto-daigaku Katsura, Nishikyo
Kyoto 615-8510 (Japan)
The presence of titanium tetraisopropoxide is crucial for
the success of the reaction. Other bases, such as sodium tert-
butoxide and cesium carbonate, did not promote the carbo-
A
ACHTUNGRTENN(UNG OTf)3, In-
Fax : (+81)75-383-2438
E-mail: oshima@orgrxn.mbox.media.kyoto-u.ac.jp
[+] Present address: Department of Chemistry
AHCTUNGTRENNUNG
Graduate School of Science
Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto 606-8502 (Japan)
Fax : (+81)75-753-3970
The choice of solvent was also an important factor in the
success of the reaction (Table 1, entries 1–7). In nonpolar
DCE and toluene and the weakly coordinating THF, 2a was
formed as the major product. On the other hand, the use of
strongly coordinating DMF and acetic acid changed product
E-mail: yori@kuchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000194.
1758
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 1758 – 1760

distribution to afford the predominant formation of lactone
3a. Acetic anhydride was also successful,[11] and finally a 1:1
mixture of DCE and Ac2O was found to afford the optimal
yield.
Palladium complexes were then screened in DCE/Ac2O
solvent (Table 1, entries 7–11). Palladium acetate and tri-
fluoroacetate was less efficient than [PdCl2ACTHNUTRGNEU(GN MeCN)2].
Simple PdCl2 was less active than its acetonitrile complex,
possibly owing to its poorer solubility. Zerovalent [Pd2
Scheme 2. Reaction of deuterium-labeled 1a.
ACHTUNGTRENNUNG
palladium complexes; therefore,
mechanism[12] is excluded.
Only hypervalent iodine compounds showed reactivity as
the oxidant. Although iodobenzene bis(trifluoroacetate) suc-
cessfully induced the reaction, the yields of 2a and 3a were
lower (11% and 23%, respectively). Other typical oxidants,
a transition-metal-free
carboacetoxylation of the olefin. As a side reaction, the for-
mation of lactone [D1]-3a predominated over the formation
of [D2]-3a[13] under the palladium catalysis, which indicates
that formal syn-carbolactonization is the major process.
A plausible mechanism that accounts for the deuterium-
labeling experiments is shown in Scheme 3. The nucleophilic
malonate moiety and olefinic moiety of (E)-[D]-1a would
such as Cu
ACHTUNGTRENNUNG(OAc)2, AgOAc, K2S2O8, and MnCAHTUNGTREN(NUGN OAc)3·2H2O
failed to induce the carboacetoxylation.
Several substrates bearing a substituent on the methylene
tether were prepared and subjected to the carboacetoxyla-
tion reaction (Table 2). The products formed were diastereo-
Table 2. Scope of Substrate. DCE=1,2-dichloroethane.
Entry
R
1
2 [%]
3 [%]
Yield of 3 [%]
d.r.
1
2
3
4
5
6
7
H
Ph
1a
1b
1c
1d
1e
1 f
1g
57
72
67
59
65
62
58
11
11
20
16
20
19
22
68
71
71
61
65
62
59
–
66:34
67:33
60:40
68:32
73:27
66:34
1-naphthyl
nBu
4-F-C6H4
4-Br-C6H4
4-MeO-C6H4
Scheme 3. Plausible reaction mechanism. (E=CO2iPr, X=Cl or OAc)
a) Reductive elimination. b) Intermolecular nucleophilic attack by an
acetate anion. c) Intramolecular nucleophilic substitution by an ester car-
bonyl group.
meric mixtures of both 2 and 3. The crude mixtures were
treated with sulfuric acid in refluxing isopropyl alcohol to
convert 2 into 3 for easy characterization. All reactions
shown in Table 2 afforded 3 in good yields. In particular, 1g,
which contained an electron-rich anisyl group, was tolerated
under the highly oxidative conditions (Table 2, entry 7). Bro-
mobenzene derivative 1 f was tolerated under these condi-
tions without undergoing oxidative addition to palladium
(Table 2, entry 6). When the corresponding ethyl ester of 1a
was used, a mixture of 2a, 3a, and their ethyl ester ana-
logues was obtained.
To investigate the reaction mechanism, monodeuterated
(E)-[D]-1a was subjected to the carboacetoxylation reaction
(Scheme 2). The carboacetoxylation product was obtained
as an 81:19 mixture of diastereomers [D1]-2a and [D2]-2a.[13]
The major isomer [D1]-2a was derived from a formal anti-
be activated by Ti
Intramolecular anti-carbopalladation would then afford 5.[14]
The oxidation of the palladium of 5 by PhI(OAc)2 would
ACHTUNGTERN(NUNG OiPr)4 and PdX2, respectively, to give 4.
AHCTUNGTRENNUNG
furnish alkyl PdIV species 6.[1,15] Reductive elimination from
6 would be the most favorable process, providing [D1]-2a as
the major product (path a). Intermolecular SN2 reaction of 6
with an acetate anion would compete, producing [D2]-2a
(path b). Lactone [D1]-3a would be formed as a byproduct
from an intramolecular SN2 lactonization reaction
(path c).[16,17]
In summary, we have developed a new approach to cyclo-
pentane derivatives using the palladium-catalyzed carboace-
toxylation of 4-pentenyl-substituted malonate esters. This
represents the first example of oxidative difunctionalization
Chem. Asian J. 2010, 5, 1758 – 1760
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1759

D. Fujino, H. Yorimitsu, and K. Oshima
COMMUNICATION
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Experimental Section
Representative procedure for the palladium-catalyzed reactions of 4-pen-
tenyl-substituted malonate esters with iodobenzene diacetate: Bis(aceto-
nitrile)dichloropalladium (7.8 mg, 0.030 mmol) and iodobenzene diace-
tate (0.19 g, 0.60 mmol) were added to a 20 mL two-necked reaction
flask. The flask was filled with argon using the standard Schlenk tech-
nique.
A mixture of 1,2-dichloroethane and acetic anhydride (1:1,
0.30 mL) was then added at room temperature. After the suspension was
stirred for 3 min, titanium tetraisopropoxide (0.10 g, 0.36 mmol) and 1a
(0.077 g 0.30 mmol, 0.30 mL of a 1:1 mixture of 1,2-dichloroethane and
acetic anhydride) were added to the flask at ambient temperature. The
mixture was heated at 508C for 20 h. After the flask was cooled to room
temperature, hydrochloric acid (1m, 5 mL) was added to quench the reac-
tion. The mixture was extracted with hexane/AcOEt (1:1, 3 x 10 mL).
The combined organic layer was then washed with aqueous sodium hy-
drogencarbonate, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The resulting residue was dissolved in isopropyl
alcohol (3.0 mL). Sulfuric acid (0.29 g, 3.0 mmol) was then added at 08C,
and the resulting mixture was heated at reflux for 2 h. After the flask was
cooled to room temperature, aqueous sodium hydrogencarbonate was
added to quench the reaction. The mixture was extracted with AcOEt
(3ꢁ10 mL each). The combined organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel with
hexane/AcOEt (5:1) as eluent to provide isopropyl 3-oxa-2-oxobicyclo-
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À
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Acknowledgements
[13] The determination of the relative stereochemistry of [D]-2a and
[D]-3a is described in Supporting Information.
[14] a) T. Pei, X. Wang, R. A. Widenhoefer, J. Am. Chem. Soc. 2003, 125,
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This work was supported by Grant-in-Aid for Scientific Research and for
GCOE Research from MEXT and the JSPS. H.Y. acknowledges financial
support from Eisai and the Uehara Memorial Foundation.
Keywords: carboacetoxylation
oxidation · palladium
· cyclization · lactones ·
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[16] The palladium-catalyzed reaction of 1a in the presence of 1.0 equiv
of lithium acetate afforded 2a and 3a in 50% and 8% yields, re-
spectively. Virtually no change in the 2a/3a ratio was observed. Fur-
ther investigation of the reaction mechanism is necessary.
[17] We confirmed that interconversion between 2 and 3 did not take
place under the reaction conditions.
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Received: March 12, 2010
Published online: June 2, 2010
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Chem. Asian J. 2010, 5, 1758 – 1760